CD138 expression is a molecular signature but not a developmental requirement for RORγt+ NKT17 cells

Abstract

Invariant NKT ( i NKT) cells are potent immunomodulatory cells that acquire effector function during their development in the thymus. IL-17–producing i NKT cells are commonly referred to as NKT17 cells, and they are unique among i NKT cells to express the heparan sulfate proteoglycan CD138 and the transcription factor RORγt. Whether and how CD138 and RORγt contribute to NKT17 cell differentiation, and whether there is an interplay between RORγt and CD138 expression to control i NKT lineage fate, remain mostly unknown. Here, we showed that CD138 expression was only associated with and not required for the differentiation and IL-17 production of NKT17 cells. Consequently, CD138-deficient mice still generated robust numbers of IL-17–producing RORγt + NKT17 cells. Moreover, forced expression of RORγt significantly promoted the generation of thymic NKT17 cells, but did not induce CD138 expression on non-NKT17 cells. These results indicated that NKT17 cell generation and IL-17 production were driven by RORγt, employing mechanisms that were independent of CD138. Therefore, our study effectively dissociated CD138 expression from the RORγt-driven molecular pathway of NKT17 cell differentiation.

Unveiling the Role of Endometrial CD-138: A Comprehensive Review on Its Significance in Infertility and Early Pregnancy

“…CD-138 is intricately associated with inflammation and immune responses. Elevated soluble CD-138 expression has been correlated with inflammation and its potential to modulate the activity of cytokines and growth factors [ 47 , 48 ]. The immune function of the endometrium is intricately regulated by hormonal changes, particularly those involving estrogen and progesterone.…”

“…Genetic and epigenetic factors intricately govern the expression of CD-138, a transmembrane protein recognized for its involvement in cell migration and cytoskeletal organization. The impact of these factors extends across a spectrum of physiological and pathological processes, notably influencing cancer, immune function, and the survival of plasma cells [ 48 ].…”

The cytokine receptor DR3 identifies and activates thymic NKT17 cells

“…While CD138 is a specific marker for NKT17 cells, CD138 is not required for their generation or effector function (Dai et al, 2015;Luo et al, 2021) Thus, functional markers for NKT17 cells are currently not available. Because cytokines play critical roles in the generation and survival of iNKT cells (Bendelac et al, 2007;Crosby et al, 2018), we screened a panel of cytokine receptors for their iNKT subset-specific expression, and here we identified the TNF receptor superfamily member 25 (TNFRS25), also known as DR3 (Meylan et al, 2011), being highly expressed on thymic NKT17 cells (Figure 1A and 1B).…”

“…Because we identified NKT17 cells based on their CD138 expression (Luo et al, 2021), we could not exclude the possibility that DR3 ligation would appear to deplete NKT17 cells by downregulating CD138 expression. In fact, the shedding of the CD138 ectodomain is a welldescribed process that results in the loss of surface CD138 (Rangarajan et al, 2020), so that DR3 ligation might have triggered CD138 downregulation without altering the composition of the thymic iNKT cells.…”

“…CD138-deficient (Sdc1 -/-) mice and RORγt Tg mice were previously described (Alexander et al, 2000;Ligons et al, 2018;Luo et al, 2021), and these animals were backcrossed in-house onto BALB/cAnNCrl background before analyses. Foxp3-DTR/EGFP mice were obtained from the Jackson Laboratory and maintained on BALB/cAnNCrl background (Lahl et al, 2007).…”